The proposal advances 1) an empirical shift to a new psychological target, background anxiety, for common symptoms of anxiety, depression, schizophrenia and autism disorders, and 2) oxytocin, a hormone which selectively diminishes background anxiety. Current theories of anxiety emphasize learning where enhanced fear conditioning, impairments in fear extinction, and the inability to control learned fear lead to anxiety problems. However, symptoms of hypervigilance and exaggerated responsivity to unpredictable threat are typically independent of the specific fear memories. Therefore, the present proposal focuses on background anxiety - a type of anxiety in threatening situations that is characterized by anxious apprehension, hypervigilance and exaggerated startle to unpredictable events, but is not directly related to learned fear. We have recently found that subcutaneously administered oxytocin, a hormone that is associated with social interaction, affiliation, stress and anxiety, reduces background anxiety without affecting learned fear in a fear-potentiated startle test in rats. Intracerebroventricular administration of oxytocin also selectively reduces background anxiety, but with a higher dose than is needed with subcutaneous delivery. Oxytocin also reduces exaggerated startle produced by social isolation demonstrating that oxytocin promotes social resiliency. The specific aims of the proposal are to investigate the generality of background anxiety and social isolation anxiety by testing oxytocin on several potentiated startle paradigms. The pharmacological selectivity of oxytocin and comparison of systemic vs. central administration will be examined by testing oxytocin agonists and antagonists on background anxiety. The potential therapeutic value of oxytocin administration will be explored by examining its long-term effects on background anxiety. Finally, the neural basis of oxytocin's reduction of background anxiety will be studied by measuring changes in mRNA expression in brain circuits related to fear and anxiety. The proposal has significance and innovation by providing evidence about oxytocin's unique antianxiety profile using experimentally rigorous fear-potentiated startle paradigms. The investigation of oxytocin as a novel antianxiety agent for a novel type of background anxiety should lead to new directions for anxiety research and therapeutics. PUBLIC HEALTH RELEVANCE: Debilitating anxious apprehension, hypervigilance, and exaggerated responsivity to threat are common to many anxiety disorders, depression, schizophrenia and autism, but are typically not helped by current antianxiety medications. Preclinical studies of exaggerated startle suggest that the hormone oxytocin has novel anti-anxiety properties specifically for these symptoms. The research on oxytocin's effects of reducing these symptoms should provide new therapeutic directions for antianxiety treatments.